The Prp8 Intein as a Target for Inhibition of Pathogenic Fungi

Z. Li1, J. Zhang1, S. Chaturvedi1, C. Green2, M. Belfort2, H. Li1

Author address: 

1Wadsworth Ctr., Albany, NY, 2Univ. at Albany, Albany, NY

Abstract: 

Abstract: Invasive fungal infections (IFIs) remain a major public health challenge. Globally, over 300 million people are affected by IFIs, with estimated deaths of over 1 million people every year. IFIs are largely caused by Candida, Cryptococcus, and Aspergillus species. Among the IFI pathogens, Cryptococcus neoformans (Cne), C. gattii (Cga), and Aspergillus fumigatus (Afu) cause significant human disease, and are difficult to treat. Currently, IFI treatment is usually achieved with combination therapy for a lengthy period of time. Despite the availability of antifungal drugs, mortality rates associated with these infections often exceed 50%. In addition, drug resistance is a significant problem. The Prp8 intein is one of the most widespread eukaryotic inteins, occurring in important pathogenic fungi including Cryptococcus and Aspergillus species. Because the processed Prp8 carries out essential and non-redundant cellular functions in pathogenic fungi, a Prp8 intein inhibitor could be a mechanistically novel anti-fungal agent. Here, we developed high throughput screening assays to monitor Prp8 splicing. Using the assays, we demonstrated that cisplatin, a broad spectrum cancer drug, not only inhibited the Prp8 splicing in vitro, but also inhibited the growth of Cne, Cga, and Afu. In contrast, Candida species that do not harbor the Prp8 intein were only poorly inhibited by cisplatin, suggesting that cisplatin inhibition is through specific targeting of the Prp8 inteins. Furthermore, the inhibitions were found as fungicidal. We also investigated the binding of cisplatin to Prp8, using mass spectrometry and mutagenesis approaches. Overall these results indicated that the Prp8 intein is a novel anti-fungal target.
2016

abstract No: 

LB-052

Full conference title: 

ASM Microbe 2016
    • ASM microbe 1st (2016)